Recent Advances in Hormonal Therapy for Advanced Prostate Cancer

More than 60 years have
elapsed since Huggins and
Hodges[1] first recognized
the hormonal dependence of prostate
cancer. The mainstay of endocrine
manipulation for metastatic adenocarcinoma
of the prostate is either orchiectomy
or medical hormone
therapy. Although the traditional definition
of "advanced" prostate cancer
encompasses patients with widespread
osteoblastic or soft-tissue metastases,
this nomenclature for advanced disease
should be challenged. A more
contemporary definition needs to be
considered in order to maximize treatment
options. This would include not
only stage D2 patients, but also men
with stages C and D1 (T3, T4, and
any T, N1) disease, a high risk of disease
recurrence after local therapy, and
prostate-specific antigen (PSA) recurrence
after local therapy.[2]

The premise of androgen ablation
relies on growth of most prostate carcinoma
cells being androgen-dependent.
The androgen receptor expressed
by these cells binds dihydrotestosterone,
which is then transported into
the nucleus, leading to a cascade of
events that induces cellular growth. If
androgen is removed, cellular death
ensues via apoptosis of the androgensensitive
cells. An androgen-independent
phenotype can occur by way
of androgen-resistant clones that survive
and proliferate, their growth being
stimulated by mitogenic growth
factors. The predomination of an androgen-
independent phenotype can
occur approximately 1 to 2 years after
the initiation of androgen deprivation.

Multiple strategies have been used
to induce serum levels of testosterone
similar to those following castration.
Traditional treatment options for androgen
blockade include orchiectomy,
luteinizing hormone-releasing hormone
(LHRH) agonists and antagonists,
nonsteroidal antiandrogens, and
estrogens. Estrogens are rarely used at
this time, owing to their potentially lifethreatening
cardiovascular toxicity and
lack of availability.[3] In the early
1980s, LHRH agonists and antiandrogens
were introduced. However, controversies
exist concerning the use of
LHRH agonists and antiandrogens,
such as the utility of combined or total
androgen blockade (ie, using an
LHRH agonist plus an antiandrogen
or orchiectomy plus an antiandrogen),
early vs delayed hormonal therapy,
and intermittent vs continuous therapy.

Risk of Disease Progression
and Death

A large percentage of men with
advanced prostate cancer have nonmetastatic
extracapsular disease (stage
T3). These individuals are at an increased
risk of dying when compared
to those with localized, organ-confined
disease.[4] A great majority of
men with T3 disease are otherwise
healthy, with minimal comorbid factors.
Most are asymptomatic but have
a substantial risk of disease progression
and death; therefore, they should
be treated in a manner similar to men
with metastatic disease. A larger subgroup
of patients would then be included,
that is, men with clinical T2
cancers would be pathologically upstaged
to T3 disease; this is appropriate
given that between 30% and 50%
of patients with clinical T2 disease
have pathologic T3 cancers.[5] A dilemma
might arise over patient selection
for treatment, but it is hard to
deny treatment to the T3 cohort, who
are at a significantly increased risk of
developing metastatic disease. Another
subgroup of patients-those with a
persistent elevation of PSA after localized
treatment by external-beam
radiation or radical prostatectomy-
also should be considered as having
advanced disease.

Recurrence Modeling
Moul[6] described the use of a recurrence
model for men treated after
radical prostatectomy, which was
based on a model by Bauer et al.[7]
Recurrence modeling appears to be
helpful in identifying men at a high
risk of disease recurrence. The Department
of Defense Center for Prostate
Disease Research model included
four prognostic factors-PSA, Gleason
sum, pathologic stage, and race-
to derive a risk of recurrence. In this
study, men in the high-risk category
(relative risk > 30) had a 55.5% chance
of recurrence at 3 years and an 84.8%
chance at 5 years.[6]

When Partin et al[8] conducted studies
in patients with stage B2 disease,
they identified a select group of patients
with a high risk of disease recurrence
after radical prostatectomy. Our
own group has developed artificial neural
networks, including the prostate calculator,
to assist with predicting
recurrence after radical prostatectomy
(www.prostatecalculator.org).[9] Although
no model can be 100% predictive,
individuals who are at a high risk
of disease recurrence may benefit from
early treatment with hormone therapy.
In the future, new and innovative biochemical
tools (eg, proteomics, protein
screening) will yield new markers that
will help clinicians not only to diagnose
prostate cancer but also to identify
patients at risk for progression and
recurrence.

Orchiectomy vs LHRH Agonists

Although orchiectomy is an excellent
modality for producing castrate
levels of testosterone, it is an underused
form of hormonal treatment. The procedure
itself is straightforward: It can
be performed in an outpatient setting
and it produces an immediate reduction
in levels of circulating testosterone
within a few hours.[10]

The first Veterans Administration
Cooperative Urological Research
Group study in 1967 illustrated that
orchiectomy was associated with a
1-year survival rate of 73% and a
5-year survival rate of 35% among
stage IV patients, vs 66% and 2%,
respectively, among patients receiving
placebo.[11] Over a longer follow-
up period, however, hormone
treatment did not have an impact on
the development or course of androgen-
independent disease.[12] Orchiectomy
did result in subjective
improvement in pain symptoms and
performance status, compared with
placebo.

Although orchiectomy and LHRH
agonists have equivalent outcomes,
most patients prefer LHRH agonists
because of the psychological problems
associated with the removal of
the testicles.[13] Another issue with
orchiectomy is the irreversible nature
of the procedure and the fact that it
can limit future therapeutic options;
for example, intermittent hormonal
ablation therapy, hypothesized to delay
the development of the androgeninsensitive
phenotype, obviously is not
possible in the setting of orchiectomy.

Data from the Prostate Cancer Outcomes
Study provided an update on
quality-of-life issues for patients receiving
hormonal therapy.[14] Those
who chose LHRH-agonist treatment
reported more sexual dysfunction
than patients who had undergone orchiectomy;
both groups had equal
baseline sexual function prior to treatment.
Again, however, the psychological
implications of loss of the
testicles may lead men to continue
choosing LHRH-agonist therapy over
orchiectomy.

LHRH Agonists

Currently, LHRH agonists seem to
be the preferred method of hormone
therapy. Since Schally et al[15] identified
the structure of gonadotropinreleasing
hormone (GnRH) in 1971,
this molecule has been of utmost importance
in the treatment of prostate
cancer. GnRH, also called LHRH, is
released from the hypothalamus in a
pulsatile fashion and exerts its effects
by stimulating the anterior pituitary
to synthesize and release luteinizing
hormone and follicle-stimulating hormone.
Luteinizing hormone attaches
to receptors on the Leydig cells of the
testes, promoting testosterone production.
Continuous exposure to LHRH
agonists eventually causes downregulation
of receptors in the pituitary,
inhibiting release of both folliclestimulating
hormone and luteinizing
hormone and diminishing testosterone
production.

The main drawback of LHRH agonists
is the initial hormonal flare,
during which the stimulation of pituitary
GnRH receptors results in an
initial surge of gonadotropins (luteinizing
hormone, follicle-stimulating
hormone) and androgens (testosterone,
dihydrotestosterone ). This flare
can result in an exacerbation of symptoms,
including increased bone pain,
urinary retention, neurologic deficits
from worsening spinal cord compression,
and ureteral obstruction.

The two most common LHRH agonists
are leuprolide (Lupron) and
goserelin acetate (Zoladex). In their
depot formulations, LHRH analogs are
easily administered, produce castrate
serum levels of testosterone within
about 1 month, and are not associated
with increased cardiovascular toxicity.
Phase III studies of LHRH agonists
vs surgical castration demonstrated no
differences in survival between the
two therapies.[16] Multiple trials with
symptomatic stage D patients have
shown improvement in or stabilization
of both local disease status and
overall performance status in nearly
all patients treated with LHRH agonist
therapy.[17,18]

LHRH Antagonists

Newer LHRH (GnRH) antagonists
under study (eg, abarelix, cetrorelix
[Cetrotide]) directly block the central
GnRH receptors in the pituitary. This
mechanism completely avoids the initial
gonadotropin and androgen surges,
ultimately producing immediate
castration with no exacerbation of
symptoms. Abarelix was compared
with leuprolide acetate in a phase III
randomized trial.[19] By day 15, medical
castrate levels of testosterone were
achieved for 75% of patients who received
abarelix, compared with 10%
of patients in the leuprolide group.
By day 29, both groups had attained
similar PSA levels.

In addition to their antagonistic effects
on the pituitary, GnRH antagonists
may exhibit direct inhibition of
androgen-independent cells in the
prostate.[20] GnRH agonists cause a
progressive rise in follicle-stimulating
hormone until it reaches baseline;
this rise in follicle-stimulating hormone
does not occur with GnRH antagonists.
It has not been clinically
established whether this follicle-stimulating
hormone-mediated role prevents
or delays the occurrence of
hormone-refractory prostate cancer,
but it offers a new possibility for treatment
modalities for hormone-refractory
disease.

Abarelix produces a rapid and large
reduction in prostate volume (30%
within 2 months) in patients receiving
the compound as neoadjuvant therapy
prior to brachytherapy or radiotherapy.
In addition, GnRH antagonists
have a reversible mode of action,
which makes them applicable for neoadjuvant
therapy or short treatment
options such as intermittent therapy.
Time and experience will be required
in order for clinicians to fully evaluate
the benefits of GnRH antagonists
vs agonists in the treatment of prostate
cancer.

Nonsteroidal Antiandrogens

About 5% to 10% of androgens
are synthesized by the adrenal glands,
which potentially can continue to stimulate
androgen-sensitive cells. The use
of nonsteroidal antiandrogens (ie, bicalutamide
[Casodex], nilutamide [Nilandron],
flutamide), which interfere
with the binding of testosterone and
dihydrotestosterone to the androgen
receptor, may offer an advantage over
monotherapy.

In a multicenter randomized trial
of 486 men with metastatic prostate
cancer, bicalutamide (50 mg/d) was
compared with hormone ablation
either by LHRH-agonist therapy or
orchiectomy.[21] The overall conclusion
was that 50 mg of bicalutamide
was not as effective as hormonal ablation
by LHRH-agonist therapy or
orchiectomy. Conventional doses of
antiandrogens are not sufficient to produce
adequate androgen deprivation
and should not be utilized as single
agents for the treatment of advanced
prostate cancer.

Combined Androgen Blockade

Based on the facts that low levels
of androgens are produced by the adrenal
glands and that monotherapy
(orchiectomy or LHRH-agonist treatment)
results in a 90% decrease in
circulating testosterone, the use of
combined androgen blockade theoretically
should be superior. Although
this topic is controversial, there is some
evidence that combination therapy improves
response and survival rates.

In 1989, the Southwest Oncology
Group (SWOG) published the first
trial showing a potential advantage of
combined androgen blockade over
monotherapy.[22] This randomized,
double-blind, placebo-controlled study
evaluated leuprolide as a single agent
vs leuprolide/flutamide in 603 men with
previously untreated, metastatic prostate
cancer. Compared with leuprolide
monotherapy, combined androgen
blockade was associated with improvement
in both median progression-free
survival (16.5 vs 13.9 months) and
median overall survival (35.6 vs 28.3
months). In addition, the use of combined
androgen blockade as initial therapy
decreased the flare phenomenon.

Other studies seem to validate these
positive findings regarding combined
androgen blockade, including the National
Cancer Institute (NCI) study
0036, European Organization for
Research and Treatment of Cancer
(EORTC) study 30853, the Canadian
Anandron Study, and the Multinational
Nilutamide Study, all of which
showed a survival benefit of 7 to 15
months with combination hormonal
therapy.[23]

Not all research findings are in
agreement about the value of combined
androgen blockade, however.
SWOG published another study (NCI
Intergroup trial 0105)[24] of 1,387
patients who were randomized to orchiectomy
plus flutamide or orchiectomy
plus placebo. They found no
survival benefit from the addition of
an antiandrogen to orchiectomy. In
addition, the Prostate Cancer Trialists'
Cooperative Group[25] published
a meta-analysis of trials using combined
androgen blockade vs monotherapy.
The analysis evaluated 27
trials and included 8,275 men. The
5-year survival rate for all patients
receiving monotherapy was 23.6%,
compared with 25.4% for combined
androgen blockade; this overall survival
difference was not statistically
significant. Studies to date have not
resulted in a consensus regarding the
clinical utility of combined androgen
blockade.

Early vs Delayed Therapy

Another topic of debate is the timing
of hormonal ablation. Does early
intervention improve survival vs delayed
intervention? Although the
question of when to initiate therapy
remains difficult, data from several
studies may assist the practitioner and
patient in making this decision.

In 1997, the Medical Research
Council (MRC)[26] of Great Britain
found that early hormonal ablation
may prolong survival, compared with
delayed treatment. This large study,
which included 938 men with locally
advanced or asymptomatic metastatic
prostate cancer, had well-matched
treatment groups: 469 men received
hormonal therapy immediately and
465 men were given hormones only
when they became symptomatic.

The MRC study demonstrated an
increase in disease-specific and overall
survival in patients treated with
immediate androgen deprivation. The
impact of immediate vs delayed hormonal
therapy on overall mortality
(including M0, MX, M1) was 62%
for the immediate treatment arm and
71% for the delayed-treatment group
(P = .02). In addition, men whose
therapy was deferred suffered significantly
more comorbid events associated
with their disease.

The Eastern Cooperative Oncology
Group[27] examined the impact of
immediate hormonal therapy on patients
with node-positive disease who
underwent radical prostatectomy and
pelvic lymphadenectomy. The men
were randomized to one of two treatment
arms (immediate androgen deprivation,
achieved by goserelin or
orchiectomy) or were followed until
disease progression.

After a median follow-up period
of 7.1 years, prostate cancer-specific
survival, progression-free survival,
and overall survival were significantly
better in the group receiving immediate
hormone therapy than in the
control group. After 10 years, the actuarial
survival of patients treated with
immediate therapy was approximately
80%, compared with 55% in the
deferred-treatment group. Thus, although
these patients were in a highrisk
category owing to their nodepositive
disease, early androgen deprivation
improved survival.

Available information suggests that
early androgen suppression for the
treatment of advanced prostate cancer
reduces disease progression and
its associated complications. Early
androgen suppression may provide a
small but statistically significant improvement
in overall survival at
10 years. Additional studies are required
to evaluate more definitively
the efficacy and adverse effects of
early vs delayed androgen suppression
in men with prostate cancer. Patients
with high-risk profiles (ie,
advanced disease) should have the
opportunity to discuss hormone-treatment
options, and treatment should
be implemented if possible.

Intermittent Androgen Blockade

Intermittent androgen blockade has
received close attention over the past
few years. The primary driving force
behind this strategy is the avoidance of
potential side effects associated with
long-term use of hormone therapy, but
intermittent androgen blockade may
also prolong the development of an
androgen-independent phenotype.

Klotz et al[28] published a study
of 20 patients with advanced prostate
cancer who were treated with intermittent
androgen blockade in the form
of diethylstilbestrol or flutamide.
Treatment was continued until a clinical
response was seen (median treatment
time: 10 months), at which point
therapy was discontinued and then restarted
after evidence of disease recurrence.
The median relapse period was
8 months after treatment interruption.
After recurrence, all patients responded
to reinitiation of hormonal ablation.

Although no large randomized
clinical trial of LHRH agonists are
available, animal and in vitro cell line
studies suggest that intermittent androgen
blockade is beneficial.[29]
Currently, the Southwest Oncology
Group, the National Cancer Institute of
Canada, the German Cancer Society,
and the South European Uro-
Oncological Group are studying the effects
of intermittent androgen blockade.

External-Beam Irradiation and
Neoadjuvant Hormonal Ablation

Multiple studies evaluating the efficacy
of adding androgen-deprivation
therapy to external-beam radiation
therapy have illustrated improved outcomes
in patients with localized or locally
advanced prostate cancer. The
Radiation Therapy Oncology Group
(RTOG)[30,31] evaluated androgen
deprivation as adjunctive therapy following
standard external-beam radiation
therapy in patients with locally
advanced prostate cancer. Patients
with clinical stage C (T3, N0, M0) or
D1 (any T, N1-3, M0) prostate cancer
were randomized to radiation plus
adjuvant LHRH agent therapy, which
was begun immediately and continued
indefinitely, or to radiation and
observation, with LHRH therapy given
only at the time of relapse.

RTOG 8531
In the RTOG 8531 trial, 977 patients
were randomized to receive
radiation only (androgen deprivation
started at disease relapse) or radiation
plus adjuvant goserelin.[30] The local
failure rate at 8 years was 23% for the
combination-therapy arm and 37% for
the radiation-alone arm (P < .0001).
Disease-free survival results favored
the immediate-androgen-deprivation
arm (P < .0001), but overall survival
was not statistically different between
the two groups (49% vs 47% at 8
years). Given that only one-fourth of
the patients have died thus far, however,
it may be too early to assess the
impact of immediate LHRH therapy
on overall survival, because there has
been insufficient time for evidence of
any survival advantage to emerge.

RTOG 8610
It is still unclear what duration of
androgen-deprivation therapy is necessary
for patients to obtain the maximal
benefit. RTOG 8610, conducted
from 1987 to 1991, randomized 471
patients with T2 to T4 tumors, with
or without pelvic lymph node involvement,
to receive radiation plus combined
androgen blockade with goserelin
and flutamide vs radiation therapy
alone.[31] Analysis at 8 years demonstrated
that patients treated with
combination therapy had improvements
in local control (12% advantage,P = .016) and disease-free
survival (12% advantage, P = .004),
as well as reductions in the incidence
of distant metastases (11% advantage,P = .04), and disease-specific mortality
(8% advantage, P = .05).

EORTC Trial
In 1997, the EORTC published a
randomized, prospective trial of 415
men (< 80 years of age) with locally
advanced disease and no previous
treatment of prostate cancer; data from
401 of those patients were available
for analysis.[32] The study, conducted
from 1987 to 1995, evaluated
external-beam radiation vs externalbeam
radiation/goserelin. The overall
5-year survival rate for men treated
with an adjuvant LHRH agonist in
addition to radiotherapy was 79%, compared
with 62% in the radiation-only
group (P = .001). At 5 years, 85% of
surviving patients in the combinedtreatment
group and 48% of the group
who received external-beam treatment
alone were free of disease (P < .001).

Evaluating Studies of Adjuvant
Hormonal Treatment
The data from the aforementioned
RTOG and EORTC trials strongly
suggest that adjuvant hormonal treatment
in patients with locally advanced
prostate cancer improves both local
control and survival. Further evaluation
will be necessary to elucidate the
optimum duration of neoadjuvant and
adjuvant hormonal therapy, the value
of such therapy in earlier-stage (T1c,
T2) disease, and the value and duration
of antiandrogens (combined androgen
blockade) in this setting.

All of these studies can be critically
challenged because they compared
radiation therapy vs radiation therapy/
androgen deprivation for a significant
period of time. No study had a
cohort receiving androgen-deprivation
monotherapy alone, however, and hormonal
therapy without radiation may
produce results similar to those seen
with combination radiation/hormonal
therapy. Furthermore, although these
studies with external-beam radiation
appear to be attractive, the value of
neoadjuvant and adjuvant hormonal
therapy in patients treated with surgery,
brachytherapy, or cryotherapy
remains unknown.

Quality-of-Life Issues

Although the efficacy of hormonal
ablation is becoming increasingly
clear, there is concern about the unknown
effects associated with years
of hormonal therapy. The most common
side effect is loss of libido, but
several other toxicities exist, including
osteopenia, hot flashes, gynecomastia,
loss of cognitive function,
fatigue/malaise, depression, and loss
of muscle mass.[33] If severe symptoms
persist, discontinuation of therapy
may be warranted.

A recent study by Herr and
O'Sullivan[33] assessed the quality of
life of asymptomatic men with nonmetastatic
prostate cancer who received
androgen-deprivation therapy. Of 144
men evaluated, 79 received androgen
deprivation and 65 did not. Androgen
deprivation consisted of orchiectomy,
leuprolide alone, or leuprolide/flutamide
(combined androgen blockade).
Fatigue, emotional distress, decreased
physical functioning, and impaired
quality of life were observed among
men who received androgen-deprivation
therapy; however, a greater adverse
effect was seen in the combined
androgen blockade group.

One recent concern is that
long-term treatment with androgen
deprivation may result in osteoporosis.[
34,35] Although one study has
suggested that osteoporosis does result
from long-term hormonal ablation,[
36] multiple groups argue that
men receiving hormonal therapy do
not have significantly lower bone mineral
densities than age-matched controls.[
37] The precise incidence of
relevant bone fractures remains unclear,
especially in regard to the potential
of osteopenia/osteoporosis
from hormonal ablation.

Conclusions

With ongoing studies, the advantages
of hormonal management for
advanced prostate cancer are becoming
evident. The traditional definition
of advanced disease should include
not only those men with widely metastatic
disease but also those with a
significant chance of progression and
risk of death from prostate cancer:
patients with stages C and D1 (T3,
T4, and any T, N1) disease, those at
high risk of disease recurrence after
local therapy, or those with PSA recurrence
after local treatment.

As new molecular markers are
identified, and with the use of relative-
risk modeling tools (eg, artificial
neural networks), an increasing number
of men can begin treatment before
metastatic disease develops. It is hoped
that earlier initiation of therapy will
reduce overall morbidity and mortality
for these patients, thereby allowing
them to have a longer symptom-free
interval and better quality of life.

Surgical castration and medical
management with GnRH analogs have
been shown to be equally effective.
Although both forms of treatment
have psychological implications, ultimately
the form of therapy selected
will be the patient's decision. Controversy
will continue regarding the clinical
utility of combination hormonal
therapy. Existing data do not uniformly
support the value of combination
therapy in improving morbidity and
survival. Currently, combined androgen
blockade and treatment with monotherapy
seem to be equally efficacious.

The optimal timing of hormonal
ablation represents another area of
controversy. Does early intervention
prevail over delayed therapy? Evidence
suggests that early androgen
suppression does reduce disease progression
and complications resulting
from progression. When patients have
high-risk profiles, clinicians should
discuss the options of early hormonal
intervention, and treatment should be
implemented if feasible. Concern
about known and unknown effects of
years of hormonal therapy use,
including the potential for osteoporosis,
has increased interest in intermittent
androgen blockade; future studies
will reveal the true efficacy of this
treatment modality.

The role of adjuvant/neoadjuvant
hormonal therapy in the setting of
external-beam radiation therapy is
becoming increasingly clear. Future
studies will need to include a cohort
with hormonal monotherapy alone,
and should identify the optimal duration
of neoadjuvant/adjuvant hormonal
treatment.

Further research will determine the
most effective treatment approaches
using hormonal and other therapies.
The combination of chemotherapy and
hormonal therapy needs to be investigated.
The ultimate goal is to identify
therapies that yield the greatest efficacy
without seriously compromising
the well-being of the patient.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.